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Methods and compositions for modulating the interaction between adiponectin and its receptorRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, In Vivo Diagnosis Or In Vivo Testing, Testing Efficacy Or Toxicity Of A Compound Or Composition (e.g., Drug, Vaccine, Etc.)Methods and compositions for modulating the interaction between adiponectin and its receptor description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060286035, Methods and compositions for modulating the interaction between adiponectin and its receptor. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates to the fields of medicine and molecular biology. In particular, the invention relates to the modulation of ligand/receptor interactions in the context of treating diseases and conditions such as obesity, anorexia nervosa, type I and type II diabetes, coronary artery disease and atherosclerosis. [0003] 2. Related Art [0004] The connection between obesity and the development of several diseases, including type II diabetes, dyslipidemia and arteriosclerosis, is well established. In the past, the adipose tissue was largely viewed as a depot for lipid. Recent observations, however, revealed that adipocytes produce and secrete several bioactive substances such as TNF.alpha., leptin, resistin, plasminogen-activator-protein I, and adiponectin. The adipose tissue is therefore not only the major storage depot for triglycerides, but also an active endocrine organ which senses metabolic signals and secrets hormones that affect whole body energy homeostasis. [0005] Adiponectin (also known as adipocyte complement-related protein (30 kDa) (Acrp30), AdipoQ, apM1, and gelatin-binding protein 28 (GBP28)) is a secreted protein of 30 kD which is produced in adipose tissue. Adiponectin is highly conserved between species. Adiponectin contains a signal sequence, a collagen like domain and a globular domain which was shown to be structurally very similar to the TNF family of proteins. The overall topology of adiponectin bears a close resemblance to the structure of the complement-related protein, C1q. (Berg et al., Trends Endocrinol Metab. 13(2):84-9. (2002)). [0006] Adiponectin forms tightly associated trimers through its globular domain. Higher oligomers are formed through interactions between collagenous triple helices of the adiponectin trimer, resulting in higher order complexes that are found circulating in the plasma (Berg et al., Trends Endocrinol Metab. 13(2):84-9. (2002)). [0007] Mouse studies have demonstrated that the serum adiponectin levels in type II diabetes mouse models are strongly reduced compared to wild-type mice, thereby providing a link between type II diabetes and adiponectin levels in the serum. The results of these studies were corroborated by human and monkey epidemiological studies which showed that adiponectin levels are significantly lower in obese than in lean subjects. Furthermore, diabetic patients were found to have strongly reduced adiponectin levels compared to non-diabetic patients. The levels of adiponectin were shown to be particularly low in diabetic patients who suffer from coronary artery disease (CAD). These serological studies provide a clear link between the adiponectin levels in the serum and the development of type II diabetes and CAD. [0008] Another correlation between low levels of adiponectin and development of type II diabetes was observed in rhesus monkeys which are predisposed to develop insulin resistance. It has been observed that the onset of insulin resistance--a hallmark of type II diabetes--is accompanied by reduced adiponectin levels in the serum. In addition, lean animals with low adiponectin levels showed a much higher degree of insulin resistance than obese animals with high levels of adiponectin. Thus, adiponectin levels rather than leanness are critical for the development of insulin resistance. Adiponectin therefore appears to have a critical role in the development of insulin resistance and type II diabetes. [0009] The importance of adiponectin levels is further emphasized by the observation that thiazolidineduiones (TZDs), which have been shown to improve blood glucose levels in several genetic models of obesity, lead to a marked increase in the adiponectin levels in the serum. [0010] Taken together, these pharmacological and serological data establish a clear link between adiponectin levels in the serum and insulin sensitivity and therefore indicate that the reduced levels of adiponectin found in type II diabetic patients may, at least in part, be responsible for the observed insulin resistance in these subjects. [0011] In addition, recent studies have shown that chronic renal failure, type 1 diabetes and anorexia nervosa are associated with increased adiponectin plasma level and reduced nonoxidative glucose metabolism (Diez et al., 2003 Eur. J. Endocrinol., 148(3), 293-300). [0012] To further understand the key role played by adiponectin in the development of diabetes, several groups have performed in vitro and in vivo studies with different type I and type II mouse models as well as obese wild-type mice. [0013] Injection of recombinant adiponectin in wild-type mice on a high fat diet was shown to substantially improve blood glucose and free fatty acid levels in the serum. Moreover, a significant weight reduction was observed in severely obese mice when administered the globular part of adiponectin over two weeks. Furthermore, the globular part of adiponectin was shown to cause an acute increase of .beta.-oxidation in isolated muscles. Similarly, a clear transient improvement of blood glucose levels was achieved by a single administration of adiponectin to ob/ob (type II diabetes) or NOD mice (type I diabetes). The fact that adiponectin can improve blood glucose levels in both types of diabetes, clearly establishes the insulin sensitizing function of adiponectin. Further, in vitro studies on isolated hepatocytes have demonstrated that adiponectin leads to an improved insulin response. Sub-physiological levels of insulin were shown to be sufficient to shut down hepatic glucose production in the presence of adiponectin. [0014] Besides its insulin sensitizing action on primary hepatocytes, adiponectin has been shown to increase free fatty acid oxidation in differentiated muscle cells and isolated muscles. Furthermore, adiponectin was shown to cause an increased expression of molecules involved in fatty acid transport, combustion and energy dissipation such as CD36, acyl-CoA oxidase (ACO) and uncoupling protein 2 (UCP2). This modulation, in turn, was shown to cause decreased tissue triglycerides content in skeletal muscles. [0015] A recent study showed that adiponectin activates AMP-activated protein kinase (AMPK). (Yamauchi et al. 2002, Nat. Med, 8(11):1288-95) In parallel with the activation of AMPK, adiponectin was shown to stimulate phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo (Yamauchi et al. 2002, Nat. Med, 8(11):1288-95). Finally, adiponectin knock-out mice have been shown to develop diet induced insulin resistance (Maeda et al., 2002, Nat med., 8(7):731-7). [0016] In summary, epidemiological studies, various experiments with diabetes mouse models and the features observed in adiponectin knock-out mice, strongly suggest an important role for adiponectin as a regulator of body energy homeostasis. Therefore, reduced adiponectin levels in the serum may be causally linked with the development of insulin resistance observed in type II diabetes. [0017] Besides its clear effects on the regulation glucose and fatty acid metabolism, several reports suggest a role for adiponectin in the development of coronary artery diseases (CAD) (Matsuda et al., 2002, J Biol Chem. 4; 277(40):37487-91;). This role is believed to be at least partly mediated by adiponectin's action on macrophages and endothelial cells. The observation that decreased adiponectin levels are associated with a higher prevalence of CAD suggested a role for adiponectin in the prevention of arteriosclerosis. Along these lines, several groups have investigated the in vitro action of adiponectin on several cell types known to be involved in the development of CAD. [0018] First, adiponectin was shown to have an effect on monocyte adhesion to endothelium, myeloid differentiation and macrophage cytokine production and phagocytosis. The reduced adhesion of monocytes to the endothelium can at least partly be attributed to adiponectin's ability to suppress TNF.alpha.-induced vascular cell adhesion molecule I (VCAM-I), endothelial leukocyte adhesion molecule-1 (E-selectin), and intracellular adhesion molecule I (ICAM-1) on human aortic endothelial cells. [0019] Furthermore, adiponectin was shown to decrease lipid accumulation in human monocyte-derived macrophages and to suppress macrophage-to-foam cell transformation. [0020] The effects of adiponectin are related to atherosclerotic plaque formation. The in vitro data suggest an anti-arterogenic property of adiponectin. Hypoadiponectinemia, therefore, might be associated with a higher incidence of vascular diseases. [0021] Moreover, adiponectin's effect on neointimal thickening after artery injury, a hallmark of arteriosclerosis, has been studied in vivo. In one study, adiponectin-deficient mice were compared to wild-type mice. Adiponectin-deficient mice showed severe neointimal thickening and increase proliferation of vascular smooth muscle cells in mechanically injured arteries, suggesting that adiponectin prevents this effect under normal circumstances. This conclusion is further corroborated by the observation that neointimal thickening in the surgical model was strongly reduced by the administration of a recombinant adenovirus expressing adiponectin (Matsuda et al, 2002, J Biol Chem. 4; 277(40):37487-91). [0022] Further studies on cultivated smooth muscle cells revealed that adiponectin inhibited DNA synthesis induced by growth factors such as PDGF, HB-EGF, bEGF and EGF, and cell proliferation and migration induced by HB-EGF. Finally, over-expression of the globular domain of adiponectin in an apoE-deficient background (an established mouse model for the development of arteriosclerosis) showed a clear improvement of arteriosclerosis (Yamauchi et al., J. Biol. Chem. 278:2461-2468 (2003)). The in vivo results further indicate a protective role of adiponectin against the development of CAD. [0023] In summary, several serological studies and in vivo and in vitro studies highlight adiponectin's important role as a regulator of lipid metabolism and insulin sensitivity as well as an anti-artherogenic factor. Continue reading about Methods and compositions for modulating the interaction between adiponectin and its receptor... 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